Food and beverage compositions infused with lipophilic active agents and methods of use thereof

ABSTRACT

Aspects described herein relate to food and beverage compositions infused with lipophilic active agents and methods of use for the treatment of a variety of disorders. More particularly, aspects described herein relate to food and beverage compositions infused with lipophilic active agents such as cannabinoids, nicotine, nonsteroidal anti-inflammatories (NSAIDs), and vitamins, that provide enhanced bioavailability of the lipophilic active agents in a subject, and that mask unpleasant tastes of lipophilic active agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/735,844 filed on Jun. 10, 2015 which claims the benefit of U.S.Provisional Application No. 62/010,601, filed Jun. 11, 2014; U.S.Provisional Application No. 62/037,706, filed Aug. 15, 2014; U.S.Provisional Patent Application No. 62/153,835 filed Apr. 28, 2015; andU.S. Provisional Patent Application No. 62/161,324 filed May 14, 2015;each of which are incorporated herein by reference in their entireties.

TECHNICAL FIELD

Aspects described herein relate to food and beverage compositionsinfused with lipophilic active agents and methods of use for thetreatment of a variety of disorders. More particularly, aspectsdescribed herein relate to food and beverage compositions infused withlipophilic active agents such as cannabinoids, nicotine, nonsteroidalanti-inflammatories (NSAIDs), and vitamins, that provide enhancedbioavailability of the lipophilic active agents in a subject, and thatmask unpleasant tastes of lipophilic active agents.

BACKGROUND

Many therapeutic agents are highly lipophilic, meaning that they aresoluble in lipids and some organic solvents while being substantiallyinsoluble or only sparsely soluble in water. The poor water-solubilityof these lipophilic agents often results in major difficulties informulation. When administered in the form of an oil solution or somekind of water and/or oil suspension or emulsion, lipophilic compoundsusually show poor bioavailability.

Various approaches to overcoming this limitation are known in the priorart. One such approach consists of dissolving a lipophilic compound in awater-miscible organic solvent such as ethanol or propylene glycol.However, when the resulting solution is admixed with blood orgastrointestinal fluids, the lipophilic compound usually precipitates asa solid or liquid emulsion, which results in a low bioavailability.Furthermore, for many lipophilic compounds no water-miscible organicsolvents exist.

Another approach involves physico-chemical solubilization techniquessuch as micellar solubilization by means of surface-active agents (i.e.,the use of surfactant micelles to solubilize and transport thetherapeutic agent). In aqueous solution, micelles can incorporatelipophilic therapeutic agents in the hydrocarbon core of the micelle, orcan entangle the agents at various positions within the micelle walls.Although micellar formulations can solubilize a variety of lipophilictherapeutic agents, the loading capacity of conventional micelleformulations is limited by the solubility of the therapeutic agent inthe micelle surfactant. For many lipophilic therapeutic agents, suchsolubility is too low to offer formulations that can delivertherapeutically effective doses.

Another method consists of preparing a derivative or an analog of thelipophilic compound having a better solubility in water than theoriginal compound. For example, this derivative may be a water-solublesalt of the compound that usually retains the original biologicalactivity. However, this approach is applicable only to compounds havingacidic or basic properties. If more substantial modifications areintroduced into the original compound to improve its solubility, adecrease or even a complete loss of the original bioactivity of thecompound is frequently observed.

Another approach consists of preparing a water-soluble pro-drug capableof liberating the original bioactive compound under physiologicalconditions. Such pro-drugs usually improve bioavailability of thecompound and can ensure a targeted delivery of the compound or itssustained release over a period of time. However, the use of pro-drugsis not universally applicable since they usually require the presence ofcertain functional groups in the original compound. In addition,synthetic methods of improving solubility of a compound by chemicalmodifications are relatively complicated and expensive.

Other methods involve the formation of complexes by the addition ofchelating agents such as citric acid, tartaric acid, amino acids,thioglycolic acid, and edetate disodium. Still other methods usebuffering agents such as acetate, citrate, glutamate, and phosphatesalts. However, buffers and chelating agents have been implicated inimparting high levels of aluminum in products, leading to adverse sideeffects. Furthermore, certain chelating agents such as EDTA have beenimplicated in adverse events such nephrotoxicity and renal tubularnecrosis.

Therefore, there is a need for improved compositions and methods for theadministration of lipophilic active agents to treat a variety ofdisorders in subjects in need thereof.

SUMMARY

To address the foregoing problems, in whole or in part, and/or otherproblems that may have been observed by persons skilled in the art, thepresent disclosure provides compositions and methods as described by wayof example as set forth below.

In one aspect, a lipophilic active agent infused food product isprovided, comprising: (a) a therapeutically effective amount of alipophilic active agent, wherein the lipophilic active agent is selectedfrom the group consisting of a cannabinoid, nicotine, a non-steroidalanti-inflammatory drug (NSAID), and a vitamin; (b) a bioavailabilityenhancing agent, wherein the bioavailability enhancing agent enhancesthe bioavailability of the lipophilic active agent; and (c) a foodproduct, wherein the food product is selected from the group consistingof tea leaves, coffee beans, cocoa powder, meats, fish, fruits,vegetables, dairy products, legumes, pastas, breads, grains, seeds,nuts, spices, and herbs. In another aspect, the lipophilic active agentinfused food product is obtainable by the steps of: (i) contacting thefood product with an oil comprising the lipophilic active agent and thebioavailability enhancing agent; and (ii) dehydrating the food product;thereby producing the lipophilic active agent infused food product. In afurther aspect, step (i) comprises saturating the food product in theoil comprising the lipophilic active agent and the bioavailabilityenhancing agent. In yet another aspect, the lipophilic active agentinfused food product further comprises a flavoring agent, particularlywherein the flavoring agent is selected from the group consisting ofvanilla, vanillin, ethyl vanillin, orange oil, peppermint oil,strawberry, raspberry, and mixtures thereof. In a further aspect, thelipophilic active agent infused food product is lyophilized.

In another aspect, a lipophilic active agent infused beverage product isprovided that is obtainable by the steps of: (i) providing lipophilicactive agent infused tea leaves, coffee beans, or cocoa powder asdescribed herein; and (ii) steeping the lipophilic active agent infusedtea leaves, coffee beans, or cocoa powder in a liquid; thereby producingthe lipophilic active agent infused beverage product.

In other aspects, a process for making a lipophilic active agent infusedfood product is provided comprising the steps of: (i) contacting a foodproduct with an oil comprising a lipophilic active agent and abioavailability enhancing agent; and (ii) dehydrating the food product;thereby producing the lipophilic active agent infused food product;wherein the lipophilic active agent infused food product comprises atherapeutically effective amount of the lipophilic active agent, andfurther wherein: (a) the lipophilic active agent is selected from thegroup consisting of a cannabinoid, nicotine, a non-steroidalanti-inflammatory drug (NSAID), and a vitamin; (b) the bioavailabilityenhancing agent enhances the bioavailability of the lipophilic activeagent; and (c) the food product is selected from the group consisting oftea leaves, coffee beans, cocoa powder, meats, fish, fruits, vegetables,dairy products, legumes, pastas, breads, grains, seeds, nuts, spices,and herbs. In another aspect, step (i) comprises saturating the foodproduct in the oil comprising the lipophilic active agent and thebioavailability enhancing agent. In another aspect, step (i) comprisescontacting the food product with a flavoring agent, particularly whereinthe flavoring agent is selected from the group consisting of vanilla,vanillin, ethyl vanillin, orange oil, peppermint oil, strawberry,raspberry, and mixtures thereof. In another aspect, the process furthercomprises a step of lyophilizing the lipophilic active agent infusedfood product. In a further aspect, wherein the lipophilic active agentinfused food product is tea leaves, the process further comprisespackaging the tea leaves in tea bags.

In another aspect, a process for making a lipophilic active agentinfused beverage product is provided comprising making lipophilic activeagent infused tea leaves, coffee beans, or cocoa powder according to anyof the processes described herein; further comprising the step ofsteeping the lipophilic active agent infused tea leaves, coffee beans,or cocoa powder in a liquid, thereby producing the lipophilic activeagent infused beverage product.

In other aspects, within the compositions and methods of the presentinvention, the lipophilic active agent is a cannabinoid. In anotheraspect, the cannabinoid is a nonpsychoactive cannabinoid such ascannabidiol.

In other aspects, within the compositions and methods of the presentinvention, the lipophilic active agent is an NSAID selected from thegroup consisting of acetylsalicylic acid, ibuprophen, acetaminophen,diclofenac, indomethacin, and piroxicam.

In other aspects, within the compositions and methods of the presentinvention, the lipophilic active agent is vitamin E.

In other aspects, the bioavailability enhancing agent within thecompositions and methods of the present invention, the lipophilic activeagent is an edible oil or fat, a protective colloid, or both aprotective colloid and an edible oil or fat. In another aspect, thebioavailability enhancing agent is also a lipophilic active agent tastemasking agent. In another particular aspect, where the bioavailabilityenhancing agent is both a protective colloid, an edible oil or fat, anda lipophilic active agent taste masking agent, the bioavailabilityenhancing agent is nonfat dry milk. In a further aspect, thebioavailability enhancing agent is substantially free of omega-6 fattyacids. In other aspects, the bioavailability of the lipophilic activeagent in a subject is at least about 1.5 times, 2 times, 5 times, or 10times greater than the bioavailability of the lipophilic active agent inthe subject in the absence of the bioavailability enhancing agent. In afurther aspect, the bioavailability of the lipophilic active agent in asubject is greater than 20%.

In a further aspect, a method of treating a condition is provided,comprising administering any of the compositions disclosed herein to asubject in need thereof. In one aspect, where the lipophilic activeagent within the compositions and methods of the invention is acannabinoid, the condition is selected from the group consisting ofcardiac diseases such as heart disease, ischemic infarcts, andcardiometabolic disorders; neurological diseases such as Alzheimer'sdisease, Parkinson's disease, schizophrenia, and Human ImmunodeficiencyVirus (HIV) dementia; obesity; metabolic disorders such as insulinrelated deficiencies and lipid profiles, hepatic diseases, diabetes, andappetite disorders; cancer chemotherapy; benign prostatic hypertrophy;irritable bowel syndrome; biliary diseases; ovarian disorders; marijuanaabuse; and alcohol, opioid, nicotine, or cocaine addiction. In anotheraspect, where the lipophilic active agent within the compositions andmethods of the invention is nicotine, the condition is anicotine-related disorder. In another aspect, where the lipophilicactive agent within the compositions and methods of the invention is anNSAID as described herein, the condition is pain, fever, and/or aninflammatory-related disease or disorder. In another aspect, where thelipophilic active agent within the compositions and methods of theinvention is a vitamin, particularly vitamin E as described herein, thecondition is vitamin E deficiency and/or a vitamin E related disease ordisorder.

In a further aspect, a method of enhancing the bioavailability of alipophilic active agent is provided, comprising heating any of thecompositions disclosed herein to a temperature that is greater than orequal to human body temperature. In some aspects, oral administration ofany of the compositions disclosed herein to a subject in need thereofresults in a heating of the compositions to a temperature that is equalto human body temperature.

Other compositions, methods, features, and advantages of the inventionwill be or will become apparent to one with skill in the art uponexamination of the following figures and detailed description. It isintended that all such additional compositions, methods, features, andadvantages be included within this description, be within the scope ofthe invention, and be protected by the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood by referring to the followingfigures. The components in the figures are not necessarily to scale,emphasis instead being placed upon illustrating the principles of theinvention. In the figures, like reference numerals designatecorresponding parts throughout the different views.

FIG. 1 is a photograph of ingredients (dry milk, tea leaves, andcannabidiol oil) used in an aspect of the present invention.

FIG. 2 is a photograph of an ingredient (dry milk) used in an aspect ofthe present invention.

FIG. 3 is a photograph of an ingredient (tea leaves) used in an aspectof the present invention.

FIG. 4 is a photograph of equipment (a food dehydrator) used in anaspect of the present invention.

FIG. 5 is a photograph of an ingredient (cannabidiol oil) used in anaspect of the present invention.

FIG. 6 is a photograph of an aspect of a composition (cannabidiolinfused tea leaves) of the present invention.

DETAILED DESCRIPTION

The present invention is directed to lipophilic active agent infusedfood and beverage compositions that provide enhanced bioavailability ina subject, particularly wherein the unpleasant taste of the lipophilicactive agent is masked. Processes for making the food and beveragecompositions are also provided, as well as methods for treatingconditions comprising administering any of the compositions disclosedherein to a subject in need thereof.

Bioavailability refers to the extent and rate at which the active moiety(drug or metabolite) enters systemic circulation, thereby accessing thesite of action. Bioavailability for a given formulation provides anestimate of the relative fraction of the orally administered dose thatis absorbed into the systemic circulation. Low bioavailability is mostcommon with oral dosage forms of poorly water-soluble, slowly absorbeddrugs. Insufficient time for absorption in the gastrointestinal tract isa common cause of low bioavailability. If the drug does not dissolvereadily or cannot penetrate the epithelial membrane (e.g., if it ishighly ionized and polar), time at the absorption site may beinsufficient. Orally administered drugs must pass through the intestinalwall and then the portal circulation to the liver, both of which arecommon sites of first-pass metabolism (metabolism that occurs before adrug reaches systemic circulation). Thus, many drugs may be metabolizedbefore adequate plasma concentrations are reached.

Bioavailability is usually assessed by determining the area under theplasma concentration-time curve (AUC). AUC is directly proportional tothe total amount of unchanged drug that reaches systemic circulation.Plasma drug concentration increases with extent of absorption; themaximum (peak) plasma concentration is reached when drug eliminationrate equals absorption rate. Peak time is the most widely used generalindex of absorption rate; the slower the absorption, the later the peaktime.

The bioavailability of some drugs is increased when co-administered withfood, particularly agents such as cannabinoids that are Class II drugsunder the Biopharmaceutical Drug Classification System (Kelepu et al.(2013) Acta Pharmaceutica Sinica B 3:361-372; Amidon et al. (1995)Pharm. Res. 12:413-420; Charman et al. (1997) J. Pharm. Sci. 86:269-282;Winstanley et al. (1989) Br. J. Clin. Pharmacol. 28:621-628). It is thelipid component of the food that plays a key role in the absorption oflipophilic drugs and that leads to enhanced oral bioavailability (Hunt &Knox (1968) J. Physiol. 194:327-336; Kelepu et al. (2013) ActaPharmaceutica Sinica B 3:361-372). This has been attributed to theability of a high fat meal to stimulate biliary and pancreaticsecretions, to decrease metabolism and efflux activity, to increaseintestinal wall permeability, and to a prolongation of gastrointestinaltract (GIT) residence time and transport via the lymphatic system(Wagnera et al. (2001) Adv. Drug Del. Rev. 50:S13-31; Kelepu et al.(2013) Acta Pharmaceutica Sinica B 3:361-372). High fat meals alsoelevate triglyceride-rich lipoproteins that associate with drugmolecules and enhance intestinal lymphatic transport, which leads tochanges in drug disposition and changes the kinetics of thepharmacological actions of poorly soluble drugs (Gershkovich et al.(2007) Eur. J. Pharm. Sci. 32:24-32; Kelepu et al. (2013) ActaPharmaceutica Sinica B 3:361-372). However, co-administration of foodwith lipophilic drugs requires close control and/or monitoring of foodintake when dosing such drugs, and can also be subject to problems withpatient compliance (Kelepu et al. (2013) Acta Pharmaceutica Sinica B3:361-372).

The present invention relates, in part, to lipophilic active agentinfused food and beverage compositions that provide enhanced lipophilicactive agent bioavailability in a subject. It was surprisingly foundthat the lipid content and colloidal properties of the lipophilic activeagent infused food and beverage compositions increased thebioavailability of the lipophilic active agents in subjects as comparedto typical oral ingestion of the lipophilic active agents. Thelipophilic active agent infused food and beverage compositions alsoallow for enhanced oral bioavailability associated with theco-administration of lipophilic drugs and lipid containing foods withoutthe dosing and compliance problems associated with administration of thelipophilic active agent in a separate formulation from the foods andbeverages. In addition, lipophilic active agents are surprisingly moreeffectively transported through the intestinal mucosa when combined withfoods and beverages that also contain antioxidants such as black tea,thereby producing a synergistic effect on lipophilic active agentabsorption and bioavailability.

The present invention also relates, in part, to lipophilic active agentinfused food and beverage compositions comprising one or more lipophilicactive agent taste masking agents. Many lipophilic active agents haveunpalatable taste profiles, which could hinder the use of orallyingested lipophilic active agents as therapeutic treatments. Inparticular, it was surprisingly found that dry milk used within theprocesses for making the lipophilic active agent infused food andbeverage compositions of the invention acted as both a bioavailabilityenhancing agent as well as a lipophilic active agent taste maskingagent.

Compositions

In one aspect, a lipophilic active agent infused food product isprovided, comprising: (a) a therapeutically effective amount of alipophilic active agent, wherein the lipophilic active agent is selectedfrom the group consisting of a cannabinoid, nicotine, a non-steroidalanti-inflammatory drug (NSAID), and a vitamin; (b) a bioavailabilityenhancing agent, wherein the bioavailability enhancing agent enhancesthe bioavailability of the lipophilic active agent; and (c) a foodproduct, wherein the food product is selected from the group consistingof tea leaves, coffee beans, cocoa powder, meats, fish, fruits,vegetables, dairy products, legumes, pastas, breads, grains, seeds,nuts, spices, and herbs. In another aspect, the lipophilic active agentinfused food product is obtainable by the steps of: (i) contacting thefood product with an oil comprising the lipophilic active agent and thebioavailability enhancing agent; and (ii) dehydrating the food product;thereby producing the lipophilic active agent infused food product. In afurther aspect, step (i) comprises saturating the food product in theoil comprising the lipophilic active agent and the bioavailabilityenhancing agent. In yet another aspect, the lipophilic active agentinfused food product further comprises a flavoring agent, particularlywherein the flavoring agent is selected from the group consisting ofvanilla, vanillin, ethyl vanillin, orange oil, peppermint oil,strawberry, raspberry, and mixtures thereof. In a further aspect, thelipophilic active agent infused food product is lyophilized.

In another aspect, a lipophilic active agent infused beverage product isprovided that is obtainable by the steps of: (i) providing lipophilicactive agent infused tea leaves, coffee beans, or cocoa powder asdescribed herein; and (ii) steeping the lipophilic active agent infusedtea leaves, coffee beans, or cocoa powder in a liquid; thereby producingthe lipophilic active agent infused beverage product.

In other aspects, the bioavailability enhancing agent within thecompositions and methods of the present invention, the lipophilic activeagent is an edible oil or fat, a protective colloid, or both aprotective colloid and an edible oil or fat. In another aspect, thebioavailability enhancing agent is also a lipophilic active agent tastemasking agent. In another particular aspect, where the bioavailabilityenhancing agent is both a protective colloid, an edible oil or fat, anda lipophilic active agent taste masking agent, the bioavailabilityenhancing agent is nonfat dry milk. In a further aspect, thebioavailability enhancing agent is substantially free of omega-6 fattyacids. In other aspects, the bioavailability of the lipophilic activeagent in a subject is at least about 1.5 times, 2 times, 5 times, or 10times greater than the bioavailability of the lipophilic active agent inthe subject in the absence of the bioavailability enhancing agent. In afurther aspect, the bioavailability of the lipophilic active agent in asubject is greater than 20%.

An edible oil is defined herein as an oil that is capable of undergoingde-esterification or hydrolysis in the presence of pancreatic lipase invivo under normal physiological conditions. Specifically, digestibleoils may be complete glycerol triesters of medium chain (C₇-C₁₃) or longchain (C₁₄-C₂₂) fatty acids with low molecular weight (up to C₆) mono-,di- or polyhydric alcohols. Some examples of digestible oils for use inthis invention thus include: vegetable, nut, or seed oils (such ascoconut oil, peanut oil, soybean oil, safflower seed oil, corn oil,olive oil, castor oil, cottonseed oil, arachis oil, sunflower seed oil,coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seedoil, wheat germ oil, sesame oil, avocado oil, almond, borage, peppermintand apricot kernel oils) and animal oils (such as fish liver oil, sharkoil and mink oil).

Examples of protective colloids include polypeptides (such as gelatin,casein, and caseinate), polysaccharides (such as starch, dextrin,dextran, pectin, and gum arabic), as well as whole milk, skimmed milk,milk powder or mixtures of these. However, it is also possible to usepolyvinyl alcohol, vinyl polymers, for example polyvinylpyrrolidone,(meth)acrylic acid polymers and copolymers, methylcellulose,carboxymethylcellulose, hydroxypropylcellulose and alginates. Forfurther details, reference may be made to R. A. Morton, Fast SolubleVitamins, Intern. Encyclopedia of Food and Nutrition, Vol. 9, PergamonPress 1970, pages 128-131.

Oral administration constitutes the preferred route of administrationfor a majority of drugs. However, drugs that have an undesirable orbitter taste leads to lack of patient compliance in the case of orallyadministered dosage forms. In such cases, taste masking is an essentialtool to improve patient compliance. Because lipophilic active agents(e.g., cannabinoids such as cannabidiol) have an undesirable tasteprofile, in order to improve compliance, the presently disclosedcompositions also comprise one or more lipophilic active agent tastemasking agents. Examples of lipophilic active agent taste-masking agentsinclude dry milk as described above, as well as menthol, sweeteners,sodium bicarbonate, ion-exchange resins, cyclodextrin inclusioncompounds, adsorbates, and the like.

In a further aspect, the bioavailability enhancing agent issubstantially free of omega-6 fatty acids.

In other aspects, the bioavailability of the lipophilic active agent ina subject is at least about 1.5 times, 2 times, 2.5 times, 3 times, 3.5times, 4 times, 4.5 times, 5 times, 5.5 times, 6 times, 6.5 times, 7times, 7.5 times, 8 times, 8.5 times, 9 times, 9.5 times, or 10 timesgreater than the bioavailability of the lipophilic active agent in thesubject in the absence of the bioavailability enhancing agent.

In a further aspect, the bioavailability of the lipophilic active agentin a subject is greater than 20% or at least about 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or greater.

Assays and methods for measuring lipophilic active agent bioavailabilityare well known in the art (see, e.g., Rocci & Jusko (1983) Comput.Programs Biomed. 16:203-215; Shargel &. Yu (1999) Appliedbiopharmaceutics & pharmacokinetics (4th ed.). New York: McGraw-Hill; Hu& Li (2011) Oral Bioavailability: Basic Principles, Advanced Concepts,and Applications, John Wiley & Sons Ltd.; Karschner et al. (2011)Clinical Chemistry 57:66-75; Ohlsson et al. (1980) Clin. Pharmacol.Ther. 28:409-416; Ohlsson et al. (1982) Biomed. Environ. Mass Spectrom.9:6-10; Ohlsson et al. (1986) Biomed. Environ. Mass Spectrom. 13:77-83;Karschner et al. (2010) Anal. Bioanal. Chem. 397:603-611).

In a further aspect, the lipophilic active agent infused food product ofthe present invention is lyophilized. Lyophilization, also known asfreeze-drying, is a process whereby water is sublimed from a compositionafter it is frozen. The frozen solution is then typically subjected to aprimary drying step in which the temperature is gradually raised undervacuum in a drying chamber to remove most of the water, and then to asecondary drying step typically at a higher temperature than employed inthe primary drying step to remove the residual moisture in thelyophilized composition. The lyophilized composition is thenappropriately sealed and stored for later use. Tang et al. (2004)Pharmaceutical Research 21:191-200 describes the scientific principlespertaining to freeze drying and guidelines for designing suitable freezedrying processes. Further description of freeze drying is found inRemington (2006) The Science and Practice of Pharmacy, 21^(st) edition,Lippincott Williams & Wilkins, pp. 828-831.

In other aspects, the compositions of the present invention furthercomprise a flavoring agent. Suitable flavoring agents include, but arenot limited to, vanilla, vanillin, ethyl vanillin, orange oil,peppermint oil, strawberry, raspberry, and mixtures thereof.

The active agents of the present invention are effective over a widedosage range. For example, in treating adult humans, compositions andmethods of the present invention comprise dosages of lipophilic activeagents from 0.01 mg to 1,000 mg, from 0.5 mg to 500 mg, from 1 mg to 100mg, from 5 mg to 50 mg, and from 10 mg to 25 mg. Alternatively, intreating adult humans, compositions and methods of the present inventioncomprise dosages of lipophilic active agents of 0.01 mg, 0.05 mg, 0.1mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg,850 mg, 900 mg, 950 mg, or 1,000 mg.

Cannabinoids

Cannabis sativa L. is one of the most widely used plants for bothrecreational and medicinal purposes. Over 500 natural constituents havebeen isolated and identified from C. sativa covering several chemicalclasses (Ahmed et al. (2008) J. Nat. Prod. 71:536-542; Ahmed et al.(2008) Tetrahedron Lett. 49:6050-6053; ElSohly & Slade (2005) Life Sci.78:539-548; Radwan et al. (2009) J. Nat. Prod. 72:906-911; Radwan et al.(2008) Planta Medica. 74:267-272; Radwan et al. (2008) J. Nat. Prod.69:2627-2633; Ross et al. (1995) Zagazig J. Pharm. Sci. 4:1-10; Turneret al. (1980) J. Nat. Prod. 43:169-170). Cannabinoids belong to thechemical class of terpenophenolics, of which at least 85 have beenuniquely identified in cannabis (Borgelt et al. (2013) Pharmacotherapy33:195-209).

Cannabinoids are ligands to cannabinoid receptors (CB₁, CB₂) found inthe human body (Pertwee (1997) Pharmacol. Ther. 74:129-180). Thecannabinoids are usually divided into the following groups: classicalcannabinoids; non-classical cannabinoids; aminoalkylindole-derivatives;and eicosanoids (Pertwee (1997) Pharmacol. Ther. 74:129-180). Classicalcannabinoids are those that have been isolated from C. sativa L. ortheir synthetic analogs. Non-classical cannabinoids are bi- ortri-cyclic analogs of tetrahydrocannabinol (THC) (without the pyranring). Aminoalkylindoles and eicosanoids are substantially different instructure compared to classical and non-classical cannabinoids. The mostcommon natural plant cannabinoids (phytocannabinoids) are cannabidiol(CBD), cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN).The most psychoactive cannabinoid is Δ⁹-THC.

In recent years, marijuana and its components have been reported inscientific literature to counter the symptoms of a broad range ofconditions including but not limited to multiple sclerosis and otherforms of muscular spasm; movement disorders; pain, including migraineheadache; glaucoma; asthma; inflammation; insomnia; and high bloodpressure. There may also be utility for cannabinoids as anxiolytics,anti-convulsives, anti-depressants, anti-psychotics, anti-cancer agents,as well as appetite stimulants. Pharmacological and toxicologicalstudies of cannabinoids have largely been focused on a synthetic analogof Δ⁹-THC (commercially available under the generic name Dronabinol). In1985, Dronabinol was approved by the FDA for the treatment ofchemotherapy associated nausea and vomiting, and later forAIDS-associated wasting and anorexia.

Therapeutic use of cannabinoids has been hampered by the psychoactiveproperties of some compounds (e.g., Dronabinol) as well as their lowbioavailability when administered orally. Bioavailability refers to theextent and rate at which the active moiety (drug or metabolite) enterssystemic circulation, thereby accessing the site of action. The lowbioavailability of orally ingested cannabinoids (from about 6% to 20%;Adams & Martin (1996) Addiction 91: 1585-614; Agurell et al. (1986)Pharmacol. Rev. 38: 21-43; Grotenhermen (2003) Clin. Pharmacokinet. 42:327-60) has been attributed to their poor dissolution properties andextensive first pass metabolism.

Cannabinoids are a heteromorphic group of chemicals which directly orindirectly activate the body's cannabinoid receptors. There are threemain types of cannabinoids: herbal cannabinoids that occur uniquely inthe cannabis plant, synthetic cannabinoids that are manufactured, andendogenous cannabinoids that are produced in vivo. Herbal cannabinoidsare nearly insoluble in water but soluble in lipids, alcohol, andnon-polar organic solvents. These natural cannabinoids are concentratedin a viscous resin that is produced in glandular structures known astrichomes. In addition to cannabinoids, the resin is rich in terpenes,which are largely responsible for the odor of the cannabis plant.

The identification of Δ⁹-tetrahydrocannabinol (THC) as a majorpsychoactive drug and its chemical synthesis in 1964 opened a new era ofsynthetic cannabinoids as pharmacological agents. Cannabinoid researchhas increased tremendously in recent years since the discovery ofcannabinoid receptors and the endogenous ligands for these receptors.The receptors include CB1, predominantly expressed in the brain, andCB2, primarily found on the cells of the immune system. Cannabinoidreceptors belong to a superfamily of G-protein-coupled receptors. Theyare single polypeptides with seven transmembrane α-helices, and have anextracellular, glycosylated N-terminus and intracellular C-terminus.Both CB1 and CB2 cannabinoid receptors are linked to G1/0-proteins. Inaddition to these receptors, endogenous ligands for these receptorscapable of mimicking the pharmacological actions of THC have also beendiscovered. Such ligands were designated endocannabinoids and includedanandamide and 2-arachidonoyl glycerol (2-AG). Anandamide is produced inthe brain and peripheral immune tissues such as the spleen.

Unlike THC, which exerts its action by binding to CB1 and CB2,cannabidiol does not bind to these receptors and hence has nopsychotropic activity. Instead, cannabidiol indirectly stimulatesendogenous cannabinoid signaling by suppressing the enzyme that breaksdown anandamide (fatty acid amide hydroxylase, “FAAH”). Cannabidiol alsostimulates the release of 2-AG. Cannabidiol has been reported to haveimmunomodulating and anti-inflammatory properties, to exhibitanticonvulsive, anti-anxiety, and antipsychotic activity, and tofunction as an efficient neuroprotective antioxidant.

Cannabinoids in cannabis are often inhaled via smoking, but may also beingested. Smoked or inhaled cannabinoids have reported bioavailabilitiesranging from 2-56%, with an average of about 30% (Huestis (2007) Chem.Biodivers. 4:1770-1804; McGilveray (2005) Pain Res. Manag. 10 Suppl.A:15A-22A). This variability is mainly due to differences in smokingdynamics. Cannabinoids that are absorbed through the mucous membranes inthe mouth (buccomucosal application) have bioavailabilities of around13% (Karschner et al. (2011) Clin. Chem. 57:66-75). By contrast, whencannabinoids are ingested, bioavailability is typically reduced to about6% (Karschner et al. (2011) Clin. Chem. 57:66-75).

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the lipophilic active agent is a cannabinoid.

In particular aspects, at least one cannabinoid within the compositionsand methods of the present invention is selected from the groupconsisting of:

In particular aspects, at least one cannabinoid within the compositionsand methods of the present invention is a non-psychoactive cannabinoidsuch as cannabidiol. In some particularly disclosed aspects, thecannabinoid is selected from the group consisting of:

where A is aryl, and particularly

but not a pinene such as:

and the R₁-R₅ groups are each independently selected from the groups ofhydrogen, lower substituted or unsubstituted alkyl, substituted orunsubstituted carboxyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alcohol, and substituted or unsubstituted ethers, andR₆-R₇ are H or methyl. In particular aspects, there are no nitrogens inthe rings, and/or no amino substitutions on the rings.

In other aspects, the cannabinoid is selected from the group consistingof:

where there can be 0 to 3 double bonds on the A ring, as indicated bythe optional double bonds indicated by dashed lines on the A ring. The Cring is aromatic, and the B ring can be a pyran. Particular aspects aredibenzo pyrans and cyclohexenyl benzenediols. Particular aspects of thecannabinoids of the present invention may also be highly lipid soluble,and in particular aspects can be dissolved in an aqueous solution onlysparingly (for example 10 mg/ml or less). The octanol/water partitionratio at neutral pH in useful aspects is 5000 or greater, for example6000 or greater. This high lipid solubility enhances penetration of thedrug into the central nervous system (CNS), as reflected by its volumeof distribution (V_(d)) of 1.5 L/kg or more, for example 3.5 L/kg, 7L/kg, or ideally 10 L/kg or more, for example at least 20 L/kg.Particular aspects may also be highly water soluble derivatives that areable to penetrate the CNS, for example carboxyl derivatives.

R₇₋₁₈ are independently selected from the group of H, substituted orunsubstituted alkyl, especially lower alkyl, for example unsubstitutedC₁-C₃ alkyl, hydroxyl, alkoxy, especially lower alkoxy such as methoxyor ethoxy, substituted or unsubstituted alcohol, and unsubstituted orsubstituted carboxyl, for example COOH or COCH₃. In other aspects R₇₋₁₈can also be substituted or unsubstituted amino, and halogen.

In particular aspects, at least one cannabinoid within the compositionsand methods of the present invention is a non-psychoactive cannabinoid,meaning that the cannabinoid has substantially no psychoactive activitymediated by the cannabinoid receptor (for example an IC₅₀ at thecannabinoid receptor of greater than or equal to 300 nM, for examplegreater than 1 μM and a K_(i) greater than 250 nM, especially 500-1000nM, for example greater than 1000 nM).

In other particular aspects, the cannabinoids within the compositionsand methods of the present invention are selected from the groupconsisting of:

where R₁₉ is substituted or unsubstituted alkyl, such as lower alkyl(for example methyl), lower alcohol (such as methyl alcohol) or carboxyl(such as carboxylic acid) and oxygen (as in ═O); R₂₀ is hydrogen orhydroxy; R₂₁ is hydrogen, hydroxy, or methoxy; R₂₂ is hydrogen orhydroxy; R₂₃ is hydrogen or hydroxy; R₂₄ is hydrogen or hydroxy; R₂₅ ishydrogen or hydroxy; and R₂₆ is substituted or unsubstituted alkyl (forexample n-methyl alkyl), substituted or unsubstituted alcohol, orsubstituted or unsubstituted carboxy.

In other particular aspects, the cannabinoids within the compositionsand methods of the present invention are selected from the groupconsisting of:

wherein numbering conventions for each of the ring positions are shown,and R₂₇, R₂₈ and R₂₉ are independently selected from the groupconsisting of H, unsubstituted lower alkyl such as CH₃, and carboxylsuch as COCH₃. Particular examples of nonpsychoactive cannabinoids thatfall within this definition are cannabidiol and

and other structural analogs of cannabidiol.

In other particular aspects, the cannabinoids within the compositionsand methods of the present invention are selected from the groupconsisting of:

wherein R₂₇, R₂₈ and R₂₉ are independently selected from the groupconsisting of H, lower alkyl such as CH₃, and carboxyl such as COCH₃,and particularly wherein:

a) R₂₇═R₂₈═R₂₉═H

b) R₂₇═R₂₉═H; R₂₈═CH₃

c) R₂₇═R₂₈═CH₃; R₂₉═H

d) R₂₇═R₂₈═COCH₃; R₂₉═H

e) R₂₇═H; R₂₈═R₂₉═COCH₃

When R₂₇═R₂₈═R₂₉═H, then the compound is cannabidiol (CBD). WhenR₂₇═R₂₉═H and R₂₈═CH₃, the compound is CBD monomethyl ether. WhenR₂₇═R₂₈═CH₃ and R₂₉═H, the compound is CBD dimethyl ether. WhenR₂₇═R₂₈═COCH₃ and R₂₉═H, the compound is CBD diacetate. When R₂₇═H andR₂₈═R₂₉═COCH₃, the compound is CBD monoacetate.

In yet another aspect, cannabinoid infused tea leaves are packaged intea bags, wherein each tea bag comprises 1 to 3 grams of tea leaves (dryweight), 0.10 to 1.0 grams of dry milk, and 10 to 25 mg of cannabinoidoil. In still another aspect, the cannabinoid infused tea leaves arepackaged in tea bags, wherein each tea bag comprises 1.5 to 12 grams oftea leaves (dry weight), 0.10 to 6.0 grams of dry milk, 10 to 25 mg ofhemp oil, and 1.0 to 12.0 grams of cannabis leaves.

Nicotine

More than 99% of all nicotine that is consumed worldwide is deliveredthrough smoking cigarettes. Approximately 6,000,000 deaths per year,worldwide, are attributed primarily to the delivery of nicotine throughthe act of smoking according to the Centers for Disease Control andPrevention, which also estimates that over $170 billion per year isspent just in the U.S. on direct medical care costs for adult smokers.In any twelve month period, 69% of U.S. adult smokers want to quitsmoking and 43% of U.S. adult smokers have attempted to quit.

Worldwide, retail cigarette sales were worth $722 billion in 2013, withover 5.7 trillion cigarettes sold to more than 1 billion smokers.

The delivery of nicotine to satisfy current demand via the compositionsand methods of the present invention (i.e., in common food groups), willalleviate the consumer demand for cigarettes. Since most of the adversehealth outcomes of nicotine consumption are associated with the deliverymethod and only to a lesser degree to the actual ingestion of nicotine,a vast positive community health outcome can be achieved through thereduction in smoking cigarettes.

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the lipophilic active agent is nicotine.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs are the second-largest category of pain management treatmentoptions in the world. The global pain management market was estimated at$22 billion in 2011, with $5.4 billion of this market being served byNSAID's. The U.S. makes up over one-half of the global market. Theopioids market (such as morphine) form the largest single painmanagement sector but are known to be associated with serious dependenceand tolerance issues.

Although NSAIDs are generally a safe and effective treatment method forpain, they have been associated with a number of gastrointestinalproblems including dyspepsia and gastric bleeding.

Delivery of NSAIDs through the compositions and methods of the presentinvention will provide the beneficial properties of pain relief withlessened negative gastrointestinal effects, and also deliver lowerdosages of active ingredients with similar pain management outcomes ascurrent pill forms at higher dosages.

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the lipophilic active agent is an NSAID,particularly wherein the NSAID is selected from the group consisting ofacetylsalicylic acid, ibuprophen, acetaminophen, diclofenac,indomethacin, and piroxicam.

Vitamins

The global vitamin and supplement market is worth $68 billion accordingto Euromonitor. The category is both broad and deep, comprised of manypopular and some lesser known substances. Vitamins in general arethought to be an $8.5 billion annual market in the U.S. The U.S. is thelargest single national market in the world, and China and Japan are the2^(nd) and 3^(rd) largest vitamin markets.

Vitamin E is fat soluble and can be incorporated into cell membraneswhich can protect them from oxidative damage. Global consumption ofnatural source vitamin E was 10,900 metric tons in 2013 worth $611.9million.

Delivery of fat soluble vitamins through the compositions and methods ofthe present invention will result in less waste and lower dosagesrequired than current pill forms. In addition, ingestion of pills is anunpleasant experience for many people so vitamin delivery through commonfood groups will vastly expand demand and use.

Accordingly, in other aspects, within the compositions and methods ofthe present invention, the lipophilic active agent is a vitamin,particularly wherein the vitamin is vitamin E.

Processes

In other aspects, a process for making a lipophilic active agent infusedfood product is provided comprising the steps of: (i) contacting a foodproduct with an oil comprising a lipophilic active agent and abioavailability enhancing agent; and (ii) dehydrating the food product;thereby producing the lipophilic active agent infused food product;wherein the lipophilic active agent infused food product comprises atherapeutically effective amount of the lipophilic active agent, andfurther wherein: (a) the lipophilic active agent is selected from thegroup consisting of a cannabinoid, nicotine, a non-steroidalanti-inflammatory drug (NSAID), and a vitamin; (b) the bioavailabilityenhancing agent enhances the bioavailability of the lipophilic activeagent; and (c) the food product is selected from the group consisting oftea leaves, coffee beans, cocoa powder, meats, fish, fruits, vegetables,dairy products, legumes, pastas, breads, grains, seeds, nuts, spices,and herbs. In another aspect, step (i) comprises saturating the foodproduct in the oil comprising the lipophilic active agent and thebioavailability enhancing agent. In another aspect, step (i) comprisescontacting the food product with a flavoring agent, particularly whereinthe flavoring agent is selected from the group consisting of vanilla,vanillin, ethyl vanillin, orange oil, peppermint oil, strawberry,raspberry, and mixtures thereof. In another aspect, the process furthercomprises a step of lyophilizing the lipophilic active agent infusedfood product.

In a further aspect, where the lipophilic active agent infused foodproduct is tea leaves, coffee beans, or cocoa powder, the processfurther comprises packaging the lipophilic active agent infused tealeaves, coffee beans, or cocoa powder in single or multiple servedelivery devices, such as tea bags, water permeable membranes,pre-packaged beverage pods such as K-CUP® packs manufactured and sold byKeurig Inc. of Wakefield, Mass., and the like. Examples include, but arenot limited to, such delivery devices and related systems as describedin U.S. Pat. Nos. 3,450,024; 5,325,765; 5,840,189; and 6,606,938.

In another aspect, a process for making a lipophilic active agentinfused beverage product is provided comprising making lipophilic activeagent infused tea leaves, coffee beans, or cocoa powder according to anyof the processes described herein; further comprising the step ofsteeping the lipophilic active agent infused tea leaves, coffee beans,or cocoa powder in a liquid, thereby producing the lipophilic activeagent infused beverage product.

Methods of Treatment

In a further aspect, a method of treating a condition is provided,comprising administering any of the compositions disclosed herein to asubject in need thereof.

In one aspect, where the lipophilic active agent within the compositionsand methods of the invention is a cannabinoid, the condition is selectedfrom the group consisting of cardiac diseases such as heart disease,ischemic infarcts, and cardiometabolic disorders; neurological diseasessuch as Alzheimer's disease, Parkinson's disease, schizophrenia, andHuman Immunodeficiency Virus (HIV) dementia; obesity; metabolicdisorders such as insulin related deficiencies and lipid profiles,hepatic diseases, diabetes, and appetite disorders; cancer chemotherapy;benign prostatic hypertrophy; irritable bowel syndrome; biliarydiseases; ovarian disorders; marijuana abuse; and alcohol, opioid,nicotine, or cocaine addiction.

In another aspect, where the lipophilic active agent within thecompositions and methods of the invention is nicotine, the condition isa nicotine-related disorder such as tobacco dependence/addiction,Parkinson's disease, ulcerative colitis, Alzheimer's disease,schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD),Tourette's syndrome, ulcerous colitis, and post-smoking-cessation weightcontrol.

In another aspect, where the lipophilic active agent within thecompositions and methods of the invention is an NSAID as describedherein, the condition is pain, fever, and/or an inflammatory-relateddisease or disorder, including but not limited to asthma, chronicobstructive pulmonary disease, pulmonary fibrosis, inflammatory boweldisease, irritable bowel syndrome, inflammatory pain, fever, migraine,headache, low back pain, fibromyalgia, myofascial disorders, viralinfections (e.g. influenza, common cold, herpes zoster, hepatitis C andAIDS), bacterial infections, fungal infections, dysmenorrhea, burns,surgical or dental procedures, malignancies (e.g. breast cancer, coloncancer, and prostate cancer), hyperprostaglandin E syndrome, classicBartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis,juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosingspondylitis, Hodgkin's disease, systemic lupus erythematosus,vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis,scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis,stroke, diabetes mellitus, neurodegenerative disorders such asAlzheimer's disease and multiple sclerosis, autoimmune diseases,allergic disorders, rhinitis, ulcers, coronary heart disease,sarcoidosis and any other disease with an inflammatory component.

In another aspect, where the lipophilic active agent within thecompositions and methods of the invention is a vitamin, the condition isa vitamin deficiency or condition associated with the lipophilicvitamin. In a particular aspect, where the vitamin is vitamin E asdescribed herein, the condition is vitamin E deficiency and/or a vitaminE related disease or disorder such as ataxia associated with vitamin Edeficiency.

In a further aspect, a method of enhancing the bioavailability of alipophilic active agent is provided, comprising heating any of thecompositions disclosed herein to a temperature that is greater than orequal to human body temperature. In some aspects, oral administration ofany of the compositions disclosed herein to a subject in need thereofresults in a heating of the compositions to a temperature that is equalto human body temperature.

In another aspect, a method of administering any of the lipophilicactive agents described herein to a subject is provided, comprising oraladministration of any of the compositions of the present invention. Suchadministration may be for any purpose, including overall health andwellness, mental acuity, alertness, recreation, and the like.

As used herein, the term “subject” treated by the presently disclosedmethods in their many aspects is desirably a human subject, although itis to be understood that the methods described herein are effective withrespect to all vertebrate species, which are intended to be included inthe term “subject.” Accordingly, a “subject” can include a human subjectfor medical purposes, such as for the diagnosis or treatment of anexisting disease, disorder, condition or the prophylactic diagnosis ortreatment for preventing the onset of a disease, disorder, or conditionor an animal subject for medical, veterinary purposes, or developmentalpurposes. Suitable animal subjects include mammals including, but notlimited to, primates, e.g., humans, monkeys, apes, gibbons, chimpanzees,orangutans, macaques and the like; bovines, e.g., cattle, oxen, and thelike; ovines, e.g., sheep and the like; caprines, e.g., goats and thelike; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses,donkeys, zebras, and the like; felines, including wild and domesticcats; canines, including dogs; lagomorphs, including rabbits, hares, andthe like; and rodents, including mice, rats, guinea pigs, and the like.An animal may be a transgenic animal. In some aspects, the subject is ahuman including, but not limited to, fetal, neonatal, infant, juvenile,and adult subjects. Further, a “subject” can include a patient afflictedwith or suspected of being afflicted with a disease, disorder, orcondition. Thus, the terms “subject” and “patient” are usedinterchangeably herein. Subjects also include animal disease models(e.g., rats or mice used in experiments, and the like).

The term “effective amount,” as in “a therapeutically effective amount,”of a therapeutic agent refers to the amount of the agent necessary toelicit the desired biological response. As will be appreciated by thoseof ordinary skill in this art, the effective amount of an agent may varydepending on such factors as the desired biological endpoint, the agentto be delivered, the composition of the pharmaceutical composition, thetarget tissue or cell, and the like. More particularly, the term“effective amount” refers to an amount sufficient to produce the desiredeffect, e.g., to reduce or ameliorate the severity, duration,progression, or onset of a disease, disorder, or condition, or one ormore symptoms thereof; prevent the advancement of a disease, disorder,or condition, cause the regression of a disease, disorder, or condition;prevent the recurrence, development, onset or progression of a symptomassociated with a disease, disorder, or condition, or enhance or improvethe prophylactic or therapeutic effect(s) of another therapy.

Actual dosage levels of the active ingredients in the presentlydisclosed compositions can be varied so as to obtain an amount of theactive ingredient that is effective to achieve the desired therapeuticresponse for a particular subject, composition, route of administration,and disease, disorder, or condition without being toxic to the subject.The selected dosage level will depend on a variety of factors includingthe activity of the particular composition employed, the route ofadministration, the time of administration, the rate of excretion of theparticular composition being employed, the duration of the treatment,other drugs, and/or materials used in combination with the particularcomposition employed, the age, sex, weight, condition, general healthand prior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician having ordinary skill in the art can readily determine andprescribe the effective amount of the presently disclosed compositionrequired. Accordingly, the dosage range for administration may beadjusted by the physician as necessary, as described more fullyelsewhere herein.

EXAMPLES Example 1

A line of CBD and/or THC infused tea bags coming in a variety of flavorswas developed.

I. Ingredients

Tea in leaf form, oil form, brewed form, organic and inorganic (FIGS. 1and 3)

Evaporated dry non-fat milk (FIGS. 1 and 2)

CBD oil (FIGS. 1 and 5)

Hemp oil or compatible oil for ingestion

Cannabis leaves, buds, oils; all strains with THC and/or CBD

II. Poppy's Formulas

II A. CBD Tea

Combine evaporated nonfat, dry milk with any and all teas, organic andinorganic

Blend CBD oil with the tea leaves

Dehydrate mixture of tea, CBD oil, and evaporated nonfat dry milk in afood dehydrator (FIG. 4)

End-product is Poppy's Tea with CBD enhancement only (FIG. 6)

II B. THC/CBD Tea

Combine evaporated nonfat, dry milk with any and all teas, organic andinorganic

Blend hemp or other ingestible oil with the tea leaves

Add cannabis leaves to above mixture

Dehydrate mixture of tea, hemp or other ingestible oil, cannabis leaves,and evaporated nonfat dry milk

End-product is Poppy's Tea with THC and CBD

III. Poppy's Formulas: Specifications

III A. CBD Tea

Tea: one tea bag contains 1 gram to 3 gramsof tea leaves (dry weight)

Evaporated dry non-fat milk: 0.10-1.00 grams

CBD oil: 10 mgs.-25 mgs. per tea bag

III B. THC/CBD Tea

Tea: one tea bag contains 1.5-12 grams tea leaves (dry weight) per teabag

Evaporated dry milk: 0.10-6.00 grams per tea bag

Hemp oil or other ingestible oil: 10 mgs.-25 mgs. per tea bag

Cannabis leaves: 1.00-12.00 grams per tea bag

III C. Production Equipment:

Commercial grinder for tea and/or cannabis leaves

Commercial mixer

Commercial dehydrator

Commercial tea bag filling machine

IV. Flavorings

Poppy's Teas will provide a menu of flavorings for addition to tea bagsor loose tea selections including, but not limited to mint, citrus, andvanilla.

Example 2

A process for adhering CBD and/or THC to food products was developed.The food products may be selected from the group consisting of meats,fish, fruits, vegetables, dairy products, legumes, pastas, breads,grains, seeds, nuts, spices, and herbs. The process may or may notinvolve contacting the food product with sunflower and/or dry evaporatedmilk. The process involved the steps of:

1. A food product was saturated with 0-60 grams of CBD and/or THC oil orextract.

2. The food product was placed on dehydrator paper and placed in a fooddehydrator for 0-24 hours.

3. The food product was removed from the dehydrator and stored inair-tight containers.

Example 3

Black tea was formulated with various lipophilic active agents. Activeagents were dosed into the tea at a concentration of approximately 4.5mg of active ingredient per gram of finished product, using non-fat drymilk and sunflower seed oil as excipients. The following ingredientswere used for the formulation:

453 g of loose leaf black tea

2265 mg active agent

45 g of instant non-fat dry evaporated milk

1132.5 mg of sunflower seed oil

Ingredients were combined in a stainless steel bowl and mixed withgloved hands.

A homogenous mixture was spread evenly on a dehydrator tray anddehydrated for 30 minutes. After cooling, the formulated tea was placedinto a sterile zip-lock bag.

The active ingredients that were formulated were: ASA (aspirin),ibuprofen, acetaminophen, diclofenac, indomethacin, piroxicam, nicotine,and vitamin E (α-tocopherol). The specific supplier information and lotnumbers for each active agent are shown below in Table 1.

TABLE 1 Active Agents Used for Formulations Cata- CAS logue CompoundNumber Supplier Number Lot Number ASA (aspirin) 50-78-2 Sigma-AldrichA2093 #MKBQ8444V Ibuprofen 15687-27-1 Sigma-Aldrich I4883 #MKBQ4505VAcetaminophen 103-90-2 Sigma-Aldrich A5000 #MKBS7142V Diclofenac15307-79-6 Sigma-Aldrich D6899 #BCBN3367V Indomethacin 53-86-1Sigma-Aldrich I8280 #MKBR4530V Piroxicam 36322-90-4 Sigma-Aldrich P0847#SLBF3478V Nicotine 54-11-5 Sigma-Aldrich N3876 #1449194V Vitamin E (α-10191-41-0 Sigma-Aldrich 258024 #MKBT5983V tocopherol)

The Tea used was loose leaf English Breakfast Tea from Upton Tea Imports(Holliston, Mass.).

The Sunflower Oil was Whole Foods brand organic sunflower oil.

The non-fat dry milk power was NowFoods brand organic non-fat dry milk.

The dehydrator used was a Presto Dehydrator, model #06300.

Each component of the formulation was weighed out and combined asdescribed in the above procedure. The weights of the individual activeagents for each formulation are summarized below in Table 2.

TABLE 2 Formulation of Active Agents Compound Non-Fat Sunflower CompoundCompound Weight Dry Milk Seed Oil Black Tea Yield Concentration ASA(aspirin) 2267.1 mg 45.09 g 1135 mg 453.2 g 479.3 g 4.52 mg/g Ibuprofen2265.5 mg 45.05 g 1138 mg 453.8 g 488.1 g 4.51 mg/g Acetaminophen 2264.7mg 45.01 g 1136 mg 453.2 g 477.9 g 4.51 mg/g Diclofenac 2265.3 mg 45.06g 1133 mg 453.1 g 441.3 g 4.52 mg/g Indomethacin 2266.3 mg 44.99 g 1138mg 453.1 g 491.5 g 4.52 mg/g Piroxicam 2265.9 mg 45.25 g 1134 mg 453.6 g488.3 g 4.51 mg/g Nicotine 2264.9 mg 45.02 g 1133 mg 453.1 g 488.1 g4.52 mg/g Vitamin E 2271.1 mg 45.05 g 1135 mg 453.2 g 480.2 g 4.53 mg/g(α-tocopherol)

For each formulation, the constituents were mixed by hand until ahomogeneous mixture was achieved, then spread evenly on dehydrator traysfor drying. Each formulation was dried for 30 minutes in dehydrator.After cooling, mixture was placed into Zip-Lock bag. After taring theanalytical balance for the Zip-Lock bag, the weight of the finalformulation was recorded and the concentration of active ingredient inthe formulation calculated (Table 2).

All publications, patent applications, patents, and other referencesmentioned in the specification are indicative of the level of thoseskilled in the art to which the presently disclosed subject matterpertains. All publications, patent applications, patents, and otherreferences are herein incorporated by reference to the same extent as ifeach individual publication, patent application, patent, and otherreference was specifically and individually indicated to be incorporatedby reference. It will be understood that, although a number of patentapplications, patents, and other references are referred to herein, suchreference does not constitute an admission that any of these documentsforms part of the common general knowledge in the art.

Although the foregoing subject matter has been described in some detailby way of illustration and example for purposes of clarity ofunderstanding, it will be understood by those skilled in the art thatcertain changes and modifications can be practiced within the scope ofthe appended claims.

What is claimed is:
 1. Cannabinoid infused tea leaves comprising: (a) atherapeutically effective amount of a cannabinoid; (b) a bioavailabilityenhancing agent comprising an edible oil comprising long chain fattyacids, wherein the bioavailability of the cannabinoid in a subject is atleast 1.5 times greater than the bioavailability of the cannabinoid inthe subject in the absence of the bioavailability enhancing agent; and(c) tea leaves; wherein the cannabinoid infused tea leaves areobtainable by the steps of: (i) contacting the tea leaves with an oilcomprising the cannabinoid and the bioavailability enhancing agent; and(ii) dehydrating the tea leaves, thereby producing the cannabinoidinfused tea leaves.
 2. The cannabinoid infused tea leaves of claim 1,wherein the bioavailability of the cannabinoid in a subject is at least3 times greater than the bioavailability of the cannabinoid in thesubject in the absence of the bioavailability enhancing agent.
 3. Thecannabinoid infused tea leaves of claim 1, wherein the bioavailabilityof the cannabinoid in a subject is at least 4.5 times greater than thebioavailability of the cannabinoid in the subject in the absence of thebioavailability enhancing agent.
 4. The cannabinoid infused tea leavesof claim 1, wherein the bioavailability enhancing agent is free ofomega-6 fatty acids.
 5. The cannabinoid infused tea leaves of claim 1,wherein the cannabinoid is a psychoactive cannabinoid.
 6. Thecannabinoid infused tea leaves of claim 1, wherein the cannabinoid is anonpsychoactive cannabinoid.
 7. The cannabinoid infused tea leaves ofclaim 1, wherein the bioavailability enhancing agent is a protectivecolloid, an edible oil or fat, and a cannabinoid taste masking agent. 8.The cannabinoid infused tea leaves of claim 7, wherein thebioavailability enhancing agent is nonfat dry milk.
 9. The cannabinoidinfused tea leaves of claim 1, further wherein the cannabinoid infusedtea leaves are lyophilized.
 10. A cannabinoid infused beverage productobtainable by the steps of: (a) contacting tea leaves with an oilcomprising a cannabinoid and a bioavailability enhancing agent; (b)dehydrating the tea leaves, thereby producing cannabinoid infused tealeaves; and (c) steeping the cannabinoid infused tea leaves in a liquid,thereby producing the cannabinoid infused beverage product; wherein thecannabinoid infused tea leaves comprise: (i) a therapeutically effectiveamount of a cannabinoid; (ii) a bioavailability enhancing agentcomprising an edible oil comprising long chain fatty acids, wherein thebioavailability of the cannabinoid in a subject is at least 1.5 timesgreater than the bioavailability of the cannabinoid in the subject inthe absence of the bioavailability enhancing agent; and (iii) tealeaves.
 11. The cannabinoid infused beverage product of claim 10,wherein the bioavailability of the cannabinoid in a subject is at least3 times greater than the bioavailability of the cannabinoid in thesubject in the absence of the bioavailability enhancing agent.
 12. Thecannabinoid infused beverage product of claim 10, wherein thebioavailability of the cannabinoid in a subject is at least 4.5 timesgreater than the bioavailability of the cannabinoid in the subject inthe absence of the bioavailability enhancing agent.
 13. The cannabinoidinfused beverage product of claim 10, wherein the bioavailabilityenhancing agent is free of omega-6 fatty acids.
 14. The cannabinoidinfused beverage product of claim 10, wherein the cannabinoid is apsychoactive cannabinoid.
 15. The cannabinoid infused beverage productof claim 10, wherein the cannabinoid is a nonpsychoactive cannabinoid.16. The cannabinoid infused beverage product of claim 10, wherein thebioavailability enhancing agent is a protective colloid, an edible oilor fat, and a cannabinoid taste masking agent.
 17. The cannabinoidinfused beverage product of claim 10, wherein the bioavailabilityenhancing agent is nonfat dry milk.
 18. The cannabinoid infused beverageproduct of claim 10, further wherein the cannabinoid infused tea leavesare lyophilized.